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Endogenous tissue transglutaminase critically regulates cardiac remodeling through distinct enzymatic and non‐enzymatic actions
Author(s) -
Shinde Arti Vijay,
Dobaczewski Marcin,
Haan Judith J,
Saxena Amit,
Lee KangKon,
Xia Ying,
Chen Wei,
Su Ya,
Palanski Brad A,
Fujikura Kana,
Garcia Mario J,
Melino Gerry,
Frangogiannis Nikolaos G
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1205.9
Subject(s) - tissue transglutaminase , extracellular matrix , matrix metalloproteinase , pressure overload , endogeny , fibrosis , ventricular remodeling , muscle hypertrophy , in vivo , enzyme , downregulation and upregulation , microbiology and biotechnology , medicine , chemistry , endocrinology , biology , heart failure , biochemistry , cardiac hypertrophy , gene
The multifunctional protein Tissue transglutaminase (tTG) is induced in remodeling tissues and regulates cellular phenotype and matrix metabolism through enzymatic (matrix cross‐linking) effects and non‐enzymatic actions. We investigated the role of endogenous tTG in cardiac remodeling and dissected the role of enzymatic and non‐enzymatic actions in vivo and in vitro. tTG expression was upregulated in the pressure‐overloaded mouse heart and was localized in the cardiomyocytes, interstitial cells and in the extracellular matrix. tTG −/− mice had increased mortality and enhanced ventricular dilation following pressure overload, but were protected from diastolic dysfunction. In vivo, tTG loss was associated with a hypercellular cardiac interstitium, reduced collagen cross‐linking, and with accentuated matrix metalloproteinase (MMP)2 activity in the pressure‐overloaded myocardium. In contrast, inhibition of tTG activity through administration of a specific small molecule inhibitor was protective, attenuating hypertrophy, fibrosis and dysfunction. In vitro, tTG did not modulate TGF‐β‐mediated responses in cardiac fibroblasts, but exerted antiproliferative actions and, when bound to the matrix, induced synthesis of tissue inhibitor of metalloproteinases (TIMP)‐1. Following pressure overload, endogenous tTG exerts enzymatic actions that increase ventricular stiffness promoting hypertrophy and fibrosis, and protective non‐enzymatic effects that prevent chamber dilation. Support or Funding Information Supported by NIH grants R01 HL76246, R01 HL85440 and R01DK63158. Dr. Shinde is supported by an American Heart Association Founders’ affiliate postdoctoral grant.